Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins

Berezovsky, Igor N.; Zeldovich, Konstantin B.; Shakhnovich, Eugene I.

doi:10.1371/journal.pcbi.0030052

Cited by 122 publications

(144 citation statements)

References 60 publications

(124 reference statements)

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“…This attribute of the genetic code is generally referred to as ‘error-minimizing'43. A related connection between the MJ matrix and pair-wise substation rates has been reported in44, where strongly-interacting pairs of amino acids are shown to substitute each other more frequently; this is attributed to correlated mutations that preserve the native structure of the protein.…”

Section: Resultsmentioning

confidence: 98%

Amino acid composition of proteins reduces deleterious impact of mutations

Hormoz

2013

Sci Rep

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The evolutionary origin of amino acid occurrence frequencies in proteins (composition) is not yet fully understood. We suggest that protein composition works alongside the genetic code to minimize impact of mutations on protein structure. First, we propose a novel method for estimating thermodynamic stability of proteins whose sequence is constrained to a fixed composition. Second, we quantify the average deleterious impact of substituting one amino acid with another. Natural proteome compositions are special in at least two ways: 1) Natural compositions do not generate more stable proteins than the average random composition, however, they result in proteins that are less susceptible to damage from mutations. 2) Natural proteome compositions that result in more stable proteins (i.e. those of thermophiles) are also tuned to have a higher tolerance for mutations. This is consistent with the observation that environmental factors selecting for more stable proteins also enhance the deleterious impact of mutations.

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Section: Resultsmentioning

confidence: 98%

Amino acid composition of proteins reduces deleterious impact of mutations

Hormoz

2013

Sci Rep

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“…Therefore, the α-subunit of human MAT II (MATα2), for which a 1.2 Å resolution crystal structure is available (PDB code 2P02), was utilized as the closest homologue. Sequence and structural changes are expected to occur between mesophilic and thermophilic homologues in order for the later to acquire their higher thermostability, and a combination of factors typically seem to contribute to this global effect [28–30]. Among the various stabilizing determinants that have been proposed for proteins from thermophiles, Mj-MAT only meets the increased percentage of charged residues (glutamic acid and lysine especially), whereas a slight decrease in hydrophobic amino acid content is also observed and the average length for MAT chains is maintained [2].…”

Section: Resultsmentioning

confidence: 99%

Subunit association as the stabilizing determinant for archaeal methionine adenosyltransferases

Garrido

Alfonso

Taylor

et al. 2009

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics

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SUMMARYArchaea contain a class of methionine adenosyltransferases (MATs) that exhibit substantially higher stability than their mesophilic counterparts. Their sequences are highly divergent, but preserve the essential active site motifs of the family. We have investigated the origin of this increased stability using chemical denaturation experiments on Methanococcus jannaschii MAT (Mj-MAT) and mutants containing single tryptophans in place of tyrosine residues. The results from fluorescence, circular dichroism, hydrodynamic, and enzyme activity measurements showed that the higher stability of Mj-MAT derives largely from a tighter association of its subunits in the dimer. Local fluorescence changes, interpreted using secondary structure predictions, further identify the least stable structural elements as the C-terminal ends of β-strands E2 and E6, and the N-terminus of E3. Dimer dissociation however requires a wider perturbation of the molecule. Additional analysis was initially hindered by the lack of crystal structures for archaeal MATs, a limitation that we overcame by construction of a 3D-homology model of Mj-MAT. This model predicts preservation of the chain topology and three-domain organization typical of this family, locates the least stable structural elements at the flat contact surface between monomers, and shows that alterations in all three domains are required for dimer dissociation.

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“…They have led to the idea that salt bridges promote hyperthermostability in proteins, whereas they make little contribution to protein stability at room temperature. This idea is supported by a lattice model which suggested that salt bridges contribute not only on the stabilization of the native states but also to the destabilization of the misfolded conformations [19]. Moreover, on the basis of temperature-dependent statistical potentials, it has been shown that not only salt bridges, but also cation- interactions, aromatic interactions, and hydrogen bonds between negatively charged and some aromatic residues tend to thermostabilize proteins, whereas hydrophobic packing appears to be neutral in this respect [20], [21].…”

Section: Introductionmentioning

confidence: 90%

Protein Thermostability Prediction within Homologous Families Using Temperature-Dependent Statistical Potentials

et al. 2014

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The ability to rationally modify targeted physical and biological features of a protein of interest holds promise in numerous academic and industrial applications and paves the way towards de novo protein design. In particular, bioprocesses that utilize the remarkable properties of enzymes would often benefit from mutants that remain active at temperatures that are either higher or lower than the physiological temperature, while maintaining the biological activity. Many in silico methods have been developed in recent years for predicting the thermodynamic stability of mutant proteins, but very few have focused on thermostability. To bridge this gap, we developed an algorithm for predicting the best descriptor of thermostability, namely the melting temperature , from the protein's sequence and structure. Our method is applicable when the of proteins homologous to the target protein are known. It is based on the design of several temperature-dependent statistical potentials, derived from datasets consisting of either mesostable or thermostable proteins. Linear combinations of these potentials have been shown to yield an estimation of the protein folding free energies at low and high temperatures, and the difference of these energies, a prediction of the melting temperature. This particular construction, that distinguishes between the interactions that contribute more than others to the stability at high temperatures and those that are more stabilizing at low , gives better performances compared to the standard approach based on -independent potentials which predict the thermal resistance from the thermodynamic stability. Our method has been tested on 45 proteins of known that belong to 11 homologous families. The standard deviation between experimental and predicted 's is equal to 13.6°C in cross validation, and decreases to 8.3°C if the 6 worst predicted proteins are excluded. Possible extensions of our approach are discussed.

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Positive and Negative Design in Stability and Thermal Adaptation of Natural Proteins

Cited by 122 publications

References 60 publications

Amino acid composition of proteins reduces deleterious impact of mutations

Amino acid composition of proteins reduces deleterious impact of mutations

Subunit association as the stabilizing determinant for archaeal methionine adenosyltransferases

Protein Thermostability Prediction within Homologous Families Using Temperature-Dependent Statistical Potentials

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